Fatigue is a multidimensional symptom that impacts 38% of community-based individuals and 42% of primary care patients. It is one of the most common and most debilitating symptoms in chronic illness and in cancer. It has significant repercussions on both direct and indirect health economic outcomes, costing an estimated annual lost productive time of US$330 million mostly due to reduced work performance. In cancer, fatigue had the greatest negative impact on daily activity, physical well-being/function, and relationships with significant others. Fatigue is described as a persistent, subjective sense of tiredness that interferes with usual functioning. It can be distinguished from normal everyday tiredness, because it is more frequent, unrelenting, unpredictable, and unresolved by rest. Fatigue may be influenced by a combination of physiological factors (e.g., inflammation or central nervous system dysfunction), psychosocial factors (e.g., depression or anxiety), and lifestyle factors (e.g., diet, exercise, alcohol use, tobacco use, or social role). Fatigue also co-occurs with other symptoms (e.g., pain, depression) contributing to symptom burden, which negatively affects health-related quality of life of patients. The etiology of fatigue is unknown, but it is believed to have central and peripheral components. Central fatigue is hypothesized to result from a decrease in central nervous system drive brought about by serotonergic pathways limiting muscle fiber recruitment during exertion reducing muscle glycolysis, oxygen consumption, and cardiovascular function. Peripheral fatigue is the inability of a particular muscle to perform a task even with an increased neural drive. This is thought to be caused by an action potential failure, cross-bridge formation impairment, or excitation contraction coupling failure amidst increased neural stimulation. The interplay between central and peripheral types of fatigue remains unclear although an increasing body of literature has indicated a potential interaction of both mechanisms. The research team continues to enroll participants for their studies that investigate the molecular-genetic correlates, as well as possible therapeutics of cancer-related fatigue. The group recently made significant discoveries related to the activation of glutamatergic receptors associated with cancer therapy that trigger inflammation that may explain the fatigue experience related to cancer therapy. Further validation is being conducted through clinical studies, animal projects and in vitro experiments. The PI is working closely with collaborators from the Multidisciplinary Prostate Cancer Clinics of the National Cancer Institute to continue to recruit study participants. The study team is also collaborating with several NIH core laboratories to further their investigations.